Advancing the prevention and treatment of HIV in children: priorities for research and development

Abrams, Elaine J.; Archary, Moherndran; Bekker, Adrie; Capparelli, Edmund V.; Colbers, Angela; Cressey, Tim R.; Frigati, Lisa; Hafiz, Asma; Mukui, Irene; Penazzato, Martina; Rakhmanina, Natella; Rojo, Pablo; Ruel, Theodore; Sam-Agudu, Nadia A.; Sugandhi, Nandita; Townsend, Claire L; Vicari, Marissa; Watkins, Melynda

doi:10.1016/s2352-3018(22)00101-1

Cited by 16 publications

(10 citation statements)

References 21 publications

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“…However, the currently available associated drugs (bictegravir and emtricitabine, or elvitegravir, cobicistat and emtricitabine) are not recommended as WHO-preferred nor alternative regimens. F/TAF may be of use in combination with dolutegravir, as a WHO-recommended alternative first-line regimen for children [8], and paediatric fixed-dose combinations of F/TAF alone and F/TAF plus dolutegravir are highlighted as priority formulations for research and development [15]. Three of the four identified studies aimed to assess pharmacokinetics, effectiveness and safety, and sample sizes were, therefore, relatively small (≤100).…”

Section: Strengths and Limitationsmentioning

confidence: 99%

“…However, limited data are available on the use of TAF in younger children, and medium‐ to long‐term safety in the paediatric population remains unknown. We, therefore, conducted a systematic review on the efficacy/effectiveness and safety of TAF in infants, children and adolescents, to inform the WHO HIV treatment guidelines updates [8] as well as the paediatric antiretroviral drug optimization process [15].…”

Section: Introductionmentioning

confidence: 99%

“…There is, therefore, a potential role for TAF as an alternative NRTI in children for first-or secondline treatment. For these reasons, TAF-based paediatric formulations have been highlighted as priority agents for public health use since 2016 [14,15].…”

Section: Introductionmentioning

confidence: 99%

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Effectiveness and safety of tenofovir alafenamide in children and adolescents living with HIV: a systematic review

et al. 2023

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Introduction: Tenofovir alafenamide (TAF) is approved for paediatric use in fixed-dose combination tablets, but efficacy and safety data in children are limited. We conducted a systematic review on the efficacy/effectiveness and safety of TAF in infants, children and adolescents living with HIV. Methods: We searched MEDLINE, Embase, the Cochrane Library, clinical trial registries, reference lists and relevant conferences to identify literature published January 2009-March 2021. We included clinical trials and observational studies assessing the efficacy/effectiveness or safety of TAF through ≥6 months of treatment in participants aged 0-19 years. Results and discussion: Overall 3626 abstracts and 371 full papers were screened. Four single-arm, innovator-funded trials (341 participants) and a pooled analysis of those trials were identified. All four trials included treatment-experienced and virally suppressed children or adolescents. One trial also included treatment-naïve adolescents with baseline viral load >1000 copies/ml. The risk of bias was rated as low in one study and unclear in the other three owing to missing data on study design (all conference presentations). At 48 weeks, 92% (46/50) of treatment-naïve participants were virally suppressed (one trial). Among treatment-experienced participants with viral load at 48 weeks, 214 of 224 participants were virally suppressed. Across the studies, one grade 3/4 adverse event was considered drug-related (intermediate uveitis). There were three discontinuations for adverse events (grade 2 anxiety and insomnia, grade 1 iridocyclitis [drug-related] and grade 1 pulmonary tuberculosis [unrelated to treatment]). One accidental death occurred across the four studies. In the pooled analysis of 223 participants, the median change in bone mineral density z-score (height-and age-adjusted) from baseline to 48 weeks was −0.12 (interquartile range [IQR] −0.46, 0.17) to 0.05 (IQR not reported) for spine, and −0.09 (IQR −0.33, 0.07) to 0.09 (IQR not reported) for total body less head. Weight-for-age z-scores increased by 0.25 from baseline to 48 weeks. Conclusions: Four single-arm trials were identified in this systematic review, with initial evidence suggesting good viral suppression and no obvious safety concerns in children and adolescents on TAF-containing regimens over 24-48 weeks. However, further comparative and longer-term safety data are needed in children and adolescents, including on weight and metabolic changes.

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Section: Strengths and Limitationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effectiveness and safety of tenofovir alafenamide in children and adolescents living with HIV: a systematic review

et al. 2023

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“…Compared with 77% of adults aged 15 years and older receiving antiretroviral treatment, only 57% of children aged 0–14 years had access to antiretroviral therapy in 2022 ( 1 ). Access to ART drugs for children was generally 7–12 years later than for adults ( 3 ). Data on the effectiveness and safety of pediatric antiretroviral regimens in the long-term treatment of children with HIV-1 were primarily based on extrapolation from adult comparative trials; however, there were limited studies on children.…”

Section: Introductionmentioning

confidence: 99%

Thirteen-year viral suppression and immunologic recovery of LPV/r-based regimens in pediatric HIV treatment: a multicenter cohort study in resource-constrained settings of China

Lao,

Zhang,

Yan

et al. 2023

Front. Med.

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BackgroundAntiretroviral Therapy (ART) in children remains challenging due to resource-constrained settings. We conducted a 13-year, prospective, multicenter cohort study on the effectiveness and safety of LPV/r-based regimens in ART-naive and ART-experienced children.MethodsFrom January 2008 to May 2021, children living with HIV-1 were recruited with LPV/r-based regimens from 8 clinical research sites in 6 provinces in China. Effectiveness outcomes were virologic failure (defined as at least two consecutive measurements of VL > 200 copies/mL after 6 months of ART) and immune response (defined as CD4% recovered to more than 25% after 12 months of treatment). The safety outcomes were treatment-related grade 2–4 adverse events and abnormal laboratory test results.ResultsA total of 345 ART-naïve children and 113 ART-experienced children were included in this cohort study. The median follow-up time was 7.3 (IQR 5.5–10.5) years. The incidence density of virologic failure was 4.1 (95% CI 3.3–4.9) per 100 person-years in ART-naïve children and 5.0 (95% CI 3.5–6.5) per 100 person-years in ART-experienced children. Kaplan Meyer (KM) curve analysis showed children with ART experience were at a higher risk of virologic failure (p < 0.05). The risk factors of virologic failure in ART-naïve children were clinic setting in rural hospitals (aHR = 2.251, 1.108–4.575), annual missed dose times >5 days of LPV intake (aHR = 1.889, 1.004–3.554); The risk factor of virologic failure in ART-experienced children was missed dose times >5 days (aHR = 2.689, 1.299–5.604) and mother as caregivers for ART administration (aHR = 0.475, 0.238–0.948). However, during long-term treatment, viral suppression rates between ART-naïve and ART-experienced children remained similar. No significant differences were observed in the immune response, treatment-related grade 2–4 events, and abnormal laboratory test results between ART-naïve children and ART-experienced children.ConclusionOur research underscores that with consistent, long-term treatment of LPV/r-based regimens, ART-experienced children can achieve therapeutic outcomes comparable to ART-naïve children. It provides crucial insights on LPV/r-based regimens in pediatric HIV treatment, especially in resource-limited settings where high-cost Integrase Strand Transfer Inhibitors (INSTs) are inaccessible. This evidence-based understanding provides an essential addition to the global therapeutic strategies for pediatric HIV treatment.

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“…To date, no systematic reviews have summarized the use of integrase inhibitors in children and adolescents. We conducted this systematic review on the effectiveness and safety of dolutegravir and raltegravir in neonates, infants, children and adolescents to support the development of the 2021 WHO consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring [ 5 ], and to inform the prioritization of future optimal drug formulations for children and adolescents [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Effectiveness and safety of dolutegravir and raltegravir for treating children and adolescents living with HIV: a systematic review

et al. 2022

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Introduction Globally about 1.7 million children were living with HIV in 2020. Two integrase strand transfer inhibitors, dolutegravir and raltegravir, are increasingly used in children. We conducted a systematic review to assess the effectiveness and safety of dolutegravir and raltegravir in children and adolescents living with HIV, aged 0–19 years. Methods Sources included MEDLINE, Embase, the Cochrane Library, clinical trial registries, abstracts from key conferences and reference list searching. Observational studies and clinical trials published January 2009–March 2021 were eligible. Outcomes included efficacy/effectiveness (CD4 counts and viral load) and/or safety outcomes (mortality, grade 3/4 adverse events and treatment discontinuation) through 6 months or more post‐treatment initiation. Risk of bias was assessed using previously published tools appropriate for the study design. Narrative syntheses were conducted. Results and discussion In total, 3626 abstracts and 371 papers were screened. Eleven studies, including 2330 children/adolescents, reported data on dolutegravir: one randomized controlled trial (RCT; low risk of bias), one single‐arm trial (unclear risk of bias) and nine cohort studies (three low risk of bias, two unclear risk and four high risk). Ten studies, including 649 children/adolescents receiving raltegravir, were identified: one RCT (low risk of bias), one single‐arm trial (low risk of bias) and eight cohort studies (four low risk of bias, three unclear risk and one high risk). Viral suppression levels in children/adolescents at 12 months were high (>70%) in most studies assessing dolutegravir (mostly second‐ or subsequent‐line, or mixed treatment lines), and varied from 42% (5/12) to 83% (44/53) at 12 months in studies assessing raltegravir (mostly second‐ or subsequent‐line). Across all studies assessing dolutegravir or raltegravir, grade 3/4 adverse events (clinical and/or laboratory) were reported in 0–50% of subjects, few resulted in discontinuation, few were drug related and no deaths were attributed to either drug. Conclusions These reassuring findings suggest that dolutegravir and raltegravir are effective and safe as preferred regimens in children and adolescents living with HIV. With the rollout of dolutegravir in paediatric populations already underway, it is critical that data are collected on safety and effectiveness in infants, children and adolescents, including on longer‐term outcomes, such as weight and metabolic changes.

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Advancing the prevention and treatment of HIV in children: priorities for research and development

Cited by 16 publications

References 21 publications

Effectiveness and safety of tenofovir alafenamide in children and adolescents living with HIV: a systematic review

Effectiveness and safety of tenofovir alafenamide in children and adolescents living with HIV: a systematic review

Thirteen-year viral suppression and immunologic recovery of LPV/r-based regimens in pediatric HIV treatment: a multicenter cohort study in resource-constrained settings of China

Effectiveness and safety of dolutegravir and raltegravir for treating children and adolescents living with HIV: a systematic review

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